The epidemic of tobacco use in industrialized societies is driven by the desire to feel the effects of nicotine which has led to an epidemic of lung cancer and heart disease in the United States and increasingly in many other countries. As is the case for chemical addiction in general, the mechanism of nicotine addiction is not known. To develop a rational theory of nicotine addiction it is necessary to understand how nicotine exerts its effects on the nervous system. During the past few years a large family of nicotinic receptors has been discovered in the brain. This discovery has revolutionized the way this excitatory receptor system is now viewed, and may explain the powerful and diverse consequences of nicotine. At the present time the only drug approved for the treatment of Alzheimer's disease is tacrin, which boosts cholinergic function which may be mediated by nicotinic receptors. The goal of the proposed research is to determine the functional roles of the many nicotinic receptor subtypes and the identification of new nicotinic receptors using a combination of gene cloning and gene knockout experiments as well as neuroanatomical and physiological techniques. Gene cloning methods will be used to discover new nicotinic receptors. The pharmacology and biophysics of the cloned nicotinic receptors will be studied by expression studies in oocytes. The pattern of expression in the nervous system will be studied by in situ hybridization and immunohistochemical methods. A recently discovered nicotinic receptor with a novel pharmacology will be studied. Each member of the family of nicotinic receptors will be mutated in the mouse by knockout technology in order to determine their functions in the nervous system. The involvement of nicotinic receptors in synaptic plasticity will be examined by determining their role in long term potentiation, long term depression and their role in spatial learning tasks. These experiments depend upon electrophysiological experiments which measure synaptic efficiency in hippocampus slice preparations and behavioral paradigms which measure learning in the mouse. The role of specific nicotinic receptors in the development of nicotine tolerance will be studied.